This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Rickettsia prowazekii is the causative agent of epidemic typhus, a vector (louse)-borne disease characterized by a sudden onset of febrile symptoms with significant pathologic sequelae. In addition to causing epidemic disease in poor and unhygienic environments, R. prowazekii has also been identified as possessing the characteristics of a biological weapon. There presently is no vaccine available for protection against epidemic typhus, although development of new products is currently underway. A fully characterized primate model of disease is needed to determine immune response, safety, and protective efficacy of vaccine products developed to protect against R. prowazekii infection. The goal of this project is to develop a robust nonhuman model of disease for epidemic typhus in order to accelerate testing of newly developed vaccine products. The specific hypothesis is that use of the Rhesus macaque (Macaca mulatta) of Chinese origin will provide an optimal test system for an infection model of epidemic typhus. We base this hypothesis upon the observations from limited past studies that detailed 1) a clear dose-response relationship in prior model development efforts with the Breinl strain using Rhesus macaques when directly compared to experimental infection with avirulent strains, and 2) typical pathology in the form of disseminated vasculitis including typhus nodules in the central nervous system that emulated the human clinical syndrome. Based on these observations, the experimental focus of this proposal is on the model development of epidemic typhus in the Rhesus macaque. The specific aims are to: 1. Reestablish a nonhuman primate model for intravenous R. prowazekii infection. Studies over 25 years ago reported on model development of R. prowazekii infection in the nonhuman primate without the benefit of advances in immunologic and physiologic measurement. We will utilize the state of the art methodology during experimental infection to achieve precise account of biological response in infected animals. This will reestablish the model in the context of immune and pathologic response for future nonhuman primate studies involving R. prowazekii infection. 2. Develop an aerosol challenge model R. prowazekii challenge. Rickettsia prowazekii, in addition to causing epidemic disease, is considered a biological threat agent because of its low dose, aerosol infectivity and history of weaponization. As such, new products must provide protective efficacy against a realistic aerosol challenge. Clinical and immunologic parameters obtained from the IV Rickettsia prowazekii infections will serve as a guide to development of the aerosol model of disease. The aerosol disease model will provide an optimal system for testing of products developed expressly for protective efficacy against potential mucosal challenge with R. prowazekii. To date, six (6) rhesus macaques have been exposed to R. prowazekii by IV injection within biocontainment. Aerosol challenges of the remaining animals on this effort are scheduled for fall 2009.